ACTIONS OF INSECTICIDES ON SODIUM CHANNEL ISOFORMS

杀虫剂对钠通道异构体的作用

• 批准号: 6043508
• 负责人: DAVID M SODERLUND
• 金额: $ 12.79万
• 依托单位: CORNELL UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 1997
• 资助国家: 美国
• 起止时间: 1997-08-09 至 2001-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6043508
• 关键词: Xenopus oocyte; animal genetic material tag; chimeric proteins; complementary DNA; gene induction /repression; human genetic material tag; molecular cloning; neurons; neurotoxicology; neurotoxins; protein isoforms; protein structure function; pyrethroid; sodium channel; voltage /patch clamp; voltage gated channel

DESCRIPTION: (Adapted from the Investigator's Abstract) Synthetic pyrethroids are an important class of neurotoxic insecticides used worldwide in agriculture and public health. Pyrethroids cause toxic effects in vertebrate nerves and muscles by modifying the normal function of voltage-sensitive sodium channels. Sodium channels exist in multiple isoforms that exhibit differential tissue distribution and developmental regulation and are encoded by members of a multigene family. Previous studies of pyrethroid action have not considered the differential sensitivity of sodium channel isoforms as a determining factor in the toxicity of these compounds. The overall objectives of the proposed research are to test the hypotheses that vertebrate sodium channel isoforms exhibit differential sensitivity to synthetic pyrethroids and that these differences in sensitivity are important determinants of the nature and severity of toxicological responses to pyrethroid exposure. Specific experimental goals are: (1) to define the actions of pyrethroid insecticides on cloned rat sodium channel isoforms expressed in Xenopus oocytes; (2) to correlate the effects of pyrethroids on sodium channel isoforms with acute and chronic neurotoxic effects; (3) to compare the actions of pyrethroids on homologous rat and human sodium channel isoforms expressed in oocytes; and (4) to map the structural determinants of differential pyrethroid sensitivity among sodium channel isoforms by the construction, heterologous functional expression and pharmacological characterization of chimeric and specifically mutated sodium channels. Cloned sodium channel isoforms will be expressed in Xenopus oocytes and the actions of pyrethroids on the channels will be assessed under voltage clamp. Results of these studies will define the role of different sodium channel isoforms in pyrethroid toxicity. Comparisons of rat and human sodium channel isoforms will determine whether rat isoforms are valid models for the sensitivity of homologous human isoforms to pyrethroids. Studies with chimeric and mutated isoforms will identify channel domains that determine pyrethroid sensitivity and will contribute to knowledge of structure-function relationships for sodium channels.

描述：（改编自研究者摘要）合成 拟除虫菊酯是世界范围内使用的一类重要的神经毒性杀虫剂 在农业和公共卫生方面。 拟除虫菊酯会引起毒性作用 通过改变脊椎动物神经和肌肉的正常功能 电压敏感钠通道。 钠通道存在于多种 表现出不同组织分布和发育的亚型 调节并由多基因家族的成员编码。 以前的 拟除虫菊酯作用的研究没有考虑差异 钠通道亚型的敏感性作为决定因素 这些化合物的毒性。 拟议的总体目标 研究目的是检验脊椎动物钠通道亚型的假设 对合成拟除虫菊酯表现出不同的敏感性，并且这些 敏感性的差异是性质的重要决定因素 拟除虫菊酯暴露的毒理学反应的严重程度。 具体的 实验目标是：（1）定义拟除虫菊酯的作用 杀虫剂对非洲爪蟾表达的克隆大鼠钠通道亚型的影响 卵母细胞； (2) 关联拟除虫菊酯对钠通道的影响 具有急性和慢性神经毒性作用的亚型； (3)比较 拟除虫菊酯对同源大鼠和人钠通道亚型的作用 在卵母细胞中表达； (4) 绘制结构决定因素 钠通道异构体之间拟除虫菊酯敏感性的差异 构建、异源功能表达和药理学 嵌合和特异性突变的钠通道的表征。 克隆的钠通道亚型将在非洲爪蟾卵母细胞中表达 将在电压钳下评估拟除虫菊酯对通道的作用。 这些研究的结果将定义不同钠通道的作用 拟除虫菊酯毒性的异构体。 大鼠和人钠的比较 通道亚型将决定大鼠亚型是否是有效模型 同源人类异构体对拟除虫菊酯的敏感性。 研究与 嵌合和突变同种型将识别决定的通道域 拟除虫菊酯敏感性，将有助于了解 钠通道的结构-功能关系。